Tag Archives: mitochondria

In Alzheimer’s disease there are problems in passing messages from neuron to neuron (impaired synaptic transmission), problems caused by a lack of energy molecules in the neurons (mitochondrial dysfunction), and problems caused by misfolded proteins which cannot be degraded by the cell, and so build up in the brain, forming abnormal protein deposits. The misfolded proteins of Alzheimer’s disease—proteins that adopt three-dimensional shapes that are dysfunctional—are beta-amyloid and tau.

Misfolded beta-amyloid protein, the primary component of the senile plaques of Alzheimer’s disease, is the topic of today’s post.

Two kinds of beta-amyloid protein

Beta-amyloid protein is found in both normal brain and Alzheimer brain. There are two primary varieties of this small protein. The most common form, only forty amino acid subunits long, is called Aβ 40. Ninety percent of all beta-amyloid is Aβ 40.

The second variety, which makes up only ten percent of the beta-amyloid in normal brain, is forty-two amino acid subunits long and is called Aβ 42. For some reason those two extra amino acid subunits cause Aβ 42 to be prone to adopting a three-dimensional shape called the beta-pleated sheet conformation. Beta-pleated sheet proteins tend to clump together into insoluble aggregates which brain cells are unable to efficiently degrade. These aggregates form in the spaces outside brain cells, and are called senile plaques.

Changes in the ratio of Aβ 42 to Aβ 40

Many tests have shown that in Alzheimer’s disease the ratio of Aβ 42 to Aβ 40 is increased, making it easier for senile plaques to form. There are three ways this could happen:

1) the brain could be producing more Aβ 42,

2) the brain could be producing less Aβ 40,

or 3) the degradation of Aβ 42 could be impaired.

(If you are thinking, “Wait a minute! Couldn’t the degradation of Aβ 40 be increased?” you are correct. But this is not a likely cause since Aβ 40 is normally degraded very effectively anyhow.)

Approaches to drug discovery concentrate on these (first) three possibilities.

Why all three?

Not every case of Alzheimer’s dementia is caused by the exact same problem(s). In fact, it seems more likely that Alzheimer’s is caused by combinations of problems, and can develop from different combinations in different people. Thus it makes sense for the researchers fighting this terrible disorder to investigate all the roads that may lead to useful treatments.

Production of Aβ 40 and Aβ 42

Beta-amyloid is a short portion of a much longer precursor protein. The precursor is simply called Amyloid Precursor Protein, or APP. It is much easier to show you how beta-amyloid is produced than to tell you. So please look carefully at the diagram below.The aqua colored rectangle represents a section of cell membrane. APP is an integral membrane protein–meaning that it runs through the membrane from one side to the other. Alpha, beta, and gamma secretase are three of the enzymes that process APP. Specifically, they cut through the APP amino acid subunit string at the points shown by the white arrows.

You will notice that alpha secretase cuts right through the middle of Aβ, destroying both the 40 and 42 forms.

Beta and Gamma secretase produce Aβ. First the beta secretase cuts the right end, and then the gamma secretase cuts the left end, freeing the Aβ.

Each of those secretases is a target for drug development. More on that next week.

By the way, what I have been sharing here is common knowledge in the field of Alzheimer’s research. To list all the people who contributed to building the knowledge we have up to this point would require, quite literally, volumes. However, if you want a reference or two to peruse, and you have access to a medical library, I would be happy to search a few down for you. Just tell me what particular portion of this information you want to pursue. Also, much of the early research on Alzheimer’s is now open access and can be read by anyone via the internet.

Last Friday, I discussed drugs that treat the synaptic dysfunction of Alzheimer’s Disease (AD). This week we will look at drugs that aim to safeguard brain neurons by protecting their energy supply. These drugs affect the function of organelles within the cell called mitochondria.

If you remember mitochondria from past Biology classes, the phrase “powerhouse of the cell” may come to mind. The function of mitochondria is to produce ATP molecules, which the cell uses as a form of stored energy.

ATP stands for adenosine-tri-phosphate—basically an adenine nucleotide with three phosphate groups attached. The phosphate groups are highly positively charged. To push three positive phosphate groups together takes a lot of energy, because objects of the same charge repel one another. So energy is used to form the bonds holding ATP together, and can be released by breaking, or cleaving, the bond holding the third phosphate in place.

When neuronal mitochondria become less effective producers of ATP, neurons don’t have the energy they need for metabolism, repair, and signaling. If mitochondrial function is badly impaired, neurons die.

Looking for drugs that protect organelle function is a new approach to treating Alzheimer’s Disease, but it makes sense. Mitochondria dysfunction occurs early in AD and promotes synaptic damage as well as neurodegeneration. Furthermore, amyloid proteins can interact with the mitochondria to cause even more impairment in the brain.

When researchers began to study mitochondria in AD, they found that some drugs already in use (Donepezil and Memantine) helped preserve mitochondial structure and enhanced mitochondrial function. How much of their effectiveness in AD is due to mitochondrial protection and how much to receptor blockade is not yet clear.

One new drug that enhances mitochondrial function is currently being tested on AD patients. Thus far it appears that this drug, Latrepirdine, is effective and improves overall well-being in people with AD.